Serine dehydratase (SDH) is an enzyme involved in gluconeogenesis, the formation of glucose, the primary fuel for cellular processes, from amino acids and certain types of fat. Gluconeogenesis usually occurs in response to a decrease in supply, or increase in demand, for glucose. SDH converts serine to pyruvate and NH.sub.4.sup.+, following a dehydration step. SDH competes with serine hydroxymethyltransferase and serine aminotransferase for available serine. (Snell et al. (1988) Br. J. Cancer 57:87-90.) SDH also catalyzes the deamination of L-threonine, preferring L-threonine at higher pH values and L-serine at lower pH values. (Pagani et al. 1989, Boll. Soc. Ital. Biol. Sper. 65: 625-629.) A variety of SDHs have been observed in organisms ranging from bacteria to vertebrates. A motif which interacts with SDH's pyridoxal 5'-phosphate cofactor in several B6 enzymes is considered characteristic of SDH. (Noda et al. 1988, FEBS Lett. 234:331-335)
SDH is synthesized primarily in the liver. (Su et al. 1992, Gene 120:301-306.) In rats, which are nocturnal feeders, SDH exhibits a circadian rhythm, reaching a maximum at the onset of darkness and a minimum at the onset of light. (Ogawa et al. 1995, Histochem. J. 27:380-387.) Variation in SDH levels appears to be generated at the level of transcription. (Ogawa et al. 1994, Arch. Biochem. Biophys. 308:285-291.) Cis-acting DNA elements required for liver-specific expression of the SDH gene have been identified. Expression of SDH mRNA in cultured hepatocytes appears to be regulated in G0/G1 transition before entry into the S phase of the cell cycle. (Noda et al., 1990, Biochem. Biophys. Res. Commun. 168:335-342.)
Gluconeogenesis is regulated by a variety of hormones responsive to such factors as age, diet, and stress. Acute hormonal regulation of liver carbohydrate metabolism mainly involves changes in cytosolic levels of cyclic adenosine monophosphate (cAMP) and Ca++(Exton, 1987, Diabetes Metab. Rev. 3:163-183). Epinephrine and glucagon both stimulate gluconeogenesis by activating adenylate cyclase in the liver plasma membrane resulting in accumulation of cAMP. cAMP up-regulates SDH transcription.
Induction of translatable mRNA for SDH in primary cultured rat hepatocytes requires both dexamethasone and glucagon or cAMP, a unique hormone requirement. Insulin and catecholamine are antagonists of SDH induction (Ichihara et al. 1982, Mol. Cell Biochem. 43:145-160.) These effects are mediated by the alpha-I adrenergic signal transfer system. The dexamethasone induction is age-dependent, apparently in correlation to the degree of methylation of the promoter region of the gene. (Bohme et al., 1987, Adv. Enzyme Regul. 26:31-61.) SDH transcription is induced in rats near birth, when their diet changes from a continuous supply of glucose via placental blood to relatively fat-rich carbohydrate-poor blood. (Bohme et al 1983 Experientia 39:473-483.)
A number of conditions and disorders involve SDH, including metabolic disorders and cancer. Gluconeogenesis from amino acids is enhanced after acute renal failure. Nephrectomized rats show significantly elevated SDH activity. Serine may play a special role as a substrate for gluconeogenesis in acute uremic rats, probably mediated by an activation of SDH. (Frohlich et al., 1977, Eur. J. Clin. Invest. 7:261-268.) Attempts have been made to develop procedures for estimation of SDH activity in blood serum to aid in detection of a variety of liver tissue impairments. (Muzhichenko et al. 1981, Vopr. Med. Khim 27:408-412.) Obese Zucker rats show significantly depressed hepatic SDH activity, and the activity does not increase in response to starvation as in lean rats. (Domenech et al. 1993, Cell. Mol. Biol. (Noisy-le-grand) 39:405-414.) SDH mRNA levels are markedly increased in streptozotocin-induced diabetes. (Ogawa, supra.) Neonatal insulin resistance which contributes to neonatal hyperglycemia has been linked to epinephrine counteracting insulin's ability to decrease SDH gene transcription. (Feng et al., 1996, Biochem. Mol. Med. 57:91-96.)
The balance of SDH, serine hydroxymethyltransferase and serine aminotransferase activities is altered in human colon carcinoma and rat sarcoma. SDH and serine aminotransferase activities are absent in human colon carcinoma and rat sarcoma, while the activity of serine hydroxymethyltransferase is markedly increased. This change may be symptomatic of the biochemical commitment to cellular replication in cancer cells. Snell et al. (supra.)
The discovery of a new serine dehydratase homolog and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, treatment, and prevention of disorders of metabolism and cancer.